Inflammatory Effector Cells Research Articles

The Role of Biochemical Markers in Cataractogenesis. Literature Review

Lens transparency is determined by both cellular and subcellular levels of its organization. Abnormalities of its size, uniformity of shape and correct arrangement of the fibers lead to the scattering of light falling on the lens. At the same time, its normal transparent proteins turn into a cloudy, coagulated, insoluble form, and undergo denaturation. Therefore, the preservation of lens transparency is possible only with a certain chemical composition, achieved by a strict balance of all metabolism links. There are many different hypotheses about the disease etiology. It is known that intraocular fluid has a low content of proteins and an increased concentration of chloride-, lactate-, ascorbatanions in its composition, in contrast to blood plasma. It cannot be ruled out that this is due to the selective permeability of the blood–ocular barrier, which consists of non-pigmented epithelial cells of the ciliary body. In addition, the modification of molecular composition and constitutional imbalance in the intraocular fluid often causes of pathological processes development in the anterior segment of the eye. The blood-ocular barrier makes the eye an immune-privileged organ. However, many diseases, surgical interventions and eye injuries can lead to blood-ocular barrier damage. This causes to inflammatory effector cells and molecules inducing a cascade of reactions, which in turn results in irreversible fibrotic changes in the lens substance. In this regard, it becomes necessary to search for new reliable methods of determining the level of certain biochemical agents in intraocular structures, as well as establishing reference values for strategically important biomarkers of cataract development. This review presents modern views on biochemical markers imbalance in the anterior chamber aqueous humor and the lens, which contributes to its substance opacity.

The link between neutrophils, NETs, and NLRP3 inflammasomes: The dual effect of CD177 and its therapeutic potential in acute respiratory distress syndrome/acute lung injury.

Neutrophils are important inflammatory effector cells that protect against foreign invasion but also cause self-harm. Numerous neutrophils infiltrate the lungs in acute respiratory distress syndrome/acute lung injury (ARDS/ALI) patients. However, the exact impact of neutrophil infiltration on ARDS's onset and progression remains unclear. To investigate this, we analyzed two ARDS-related datasets from the Gene Expression Omnibus public database and discovered an association between CD177, a neutrophil-specific surface protein, and ARDS progression. We used quantitative flow cytometry to assess CD177+ neutrophils in the peripheral blood of clinical ARDS patients vs healthy controls, finding a significant increase in CD177+ neutrophils percentage among total neutrophils in ARDS patients. This finding was further confirmed in ALI mouse models. Subsequent animal experiments showed that anti-CD177 effectively reduces pulmonary edema, neutrophil infiltration, and inflammatory cytokine release, along with a decrease in reactive oxygen species (ROS) and myeloperoxidase (MPO) levels. We also established an in vitro co-culture system to mimic neutrophil and lung epithelial cell interactions. In the anti-CD177 group, we observed decreased expression of NLRP3, caspase 1, peptidyl arginine deiminase (PAD4), MPO, and ROS, along with a reduction in certain inflammatory cytokines. These results indicate a crucial role for the CD177 gene in ARDS's development and progression. Inhibiting CD177 may help mitigate excessive activation of NLRP3 inflammasomes, ROS, and neutrophil extracellular traps (NETs), thus alleviating ARDS.

LIGHT/TNFSF14 Affects Adipose Tissue Phenotype.

LIGHT/TNFSF14 is linked to several signaling pathways as a crucial member of a larger immunoregulatory network. It is primarily expressed in inflammatory effector cells, and high levels of LIGHT have been reported in obesity. Thus, with the aim of deepening the knowledge of the role of LIGHT on adipose tissue phenotype, we studied wild-type (WT), Tnfsf14-/-, Rag-/- and Rag-/Tnfsf14- (DKO) mice fed a normal diet (ND) or high-fat diet (HFD). Our results show that, although there is no significant weight gain between the mice with different genotypes, it is significant within each of them. We also detected an increase in visceral White Adipose Tissue (vWAT) weight in all mice fed HFD, together with the lowest levels of vWAT weight in Tnfsf14-/- and DKO mice fed ND with respect to the other strain. Inguinal WAT (iWAT) weight is significantly affected by genotype and HFD. The least amount of iWAT was detected in DKO mice fed ND. Histological analysis of vWAT showed that both the genotype and the diet significantly affect the adipocyte area, whereas the number is affected only by the genotype. In iWAT, the genotype and the diet significantly affect mean adipocyte area and number; interestingly, the area with the least adipocyte was detected in DKO mice fed ND, suggesting a potential browning effect due to the simultaneous lack of mature lymphocytes and LIGHT. Consistently, Uncoupling Protein 1 (UCP1) staining of iWAT demonstrated that few positive brown adipocytes appeared in DKO mice. Furthermore, LIGHT deficiency is associated with greater levels of UCP1, highlighting the lack of its expression in Rag-/- mice. Liver examination showed that all mice fed HFD had a steatotic liver, but it was particularly evident for DKO mice. In conclusion, our study demonstrates that the adipose tissue phenotype is affected by LIGHT levels but also much more by mature lymphocytes.

Blood Monocyte Phenotype Is A Marker of Cardiovascular Risk in Type 2 Diabetes.

Diabetes is a major risk factor for atherosclerotic cardiovascular diseases with a 2-fold higher risk of cardiovascular events in people with diabetes compared with those without. Circulating monocytes are inflammatory effector cells involved in both type 2 diabetes (T2D) and atherogenesis. We investigated the relationship between circulating monocytes and cardiovascular risk progression in people with T2D, using phenotypic, transcriptomic, and metabolomic analyses. cardiovascular risk progression was estimated with coronary artery calcium score in a cohort of 672 people with T2D. Coronary artery calcium score was positively correlated with blood monocyte count and frequency of the classical monocyte subtype. Unsupervised k-means clustering based on monocyte subtype profiles revealed 3 main endotypes of people with T2D at varying risk of cardiovascular events. These observations were confirmed in a validation cohort of 279 T2D participants. The predictive association between monocyte count and major adverse cardiovascular events was validated through an independent prospective cohort of 757 patients with T2D. Integration of monocyte transcriptome analyses and plasma metabolomes showed a disruption of mitochondrial pathways (tricarboxylic acid cycle, oxidative phosphorylation pathway) that underlined a proatherogenic phenotype. In this study, we provide evidence that frequency and monocyte phenotypic profile are closely linked to cardiovascular risk in patients with T2D. The assessment of monocyte frequency and count is a valuable predictive marker for risk of cardiovascular events in patients with T2D. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04353869.

Amelioration of experimental autoimmune encephalomyelitis by in vivo reprogramming of macrophages using pro-resolving factors

BackgroundReinstating inflammation resolution represents an innovative concept to regain inflammation control in diseases marked by chronic inflammation. While most therapeutics target inflammatory molecules and inflammatory effector cells and mediators, targeting macrophages to initiate inflammation resolution to control neuroinflammation has not yet been attempted. Resolution-phase macrophages are critical in the resolution process to regain tissue homeostasis, and are programmed through the presence and elimination of apoptotic leukocytes. Hence, inducing resolution-phase macrophages might represent an innovative therapeutic approach to control and terminate dysregulated neuroinflammation.MethodsHere, we investigated if the factors released by in vitro induced resolution-phase macrophages (their secretome) are able to therapeutically reprogram macrophages to control neuroinflammation in the model of experimental autoimmune encephalomyelitis (EAE).ResultsWe found that injection of the pro-resolutive secretome reduced demyelination and decreased inflammatory cell infiltration in the CNS, notably through the in vivo reprogramming of macrophages at the epigenetic level. Adoptive transfer experiments with in vivo or in vitro reprogrammed macrophages using such pro-resolutive secretome confirmed the stability and transferability of this acquired therapeutic activity.ConclusionsOverall, our data confirm the therapeutic activity of a pro-resolution secretome in the treatment of ongoing CNS inflammation, via the epigenetic reprogramming of macrophages and open with that a new therapeutic avenue for diseases marked by neuroinflammation.

Systemic administration of STING agonist promotes myeloid cells maturation and antitumor immunity through regulating hematopoietic stem and progenitor cell fate.

STING is a pivotal mediator of effective innate and adaptive anti-tumor immunity; however, intratumoral administration of STING agonists have shown limited therapeutic benefit in clinical trials. The systemic effect of the intravenous delivery of STING agonists in cancer is not well-defined. Here, we demonstrated that systemic administration of STING agonist inhibited melanoma growth, improved inflammatory effector cell infiltration, and induced bone marrow mobilization and extramedullary hematopoiesis, causing widespread changes in immune components in the peripheral blood. The systemically administered STING agonist promoted HSC expansion and influenced lineage fate commitment, which was manifested as the differentiation of HSPCs was skewed toward myeloid cells at the expense of B-cell lymphopoiesis and erythropoiesis. Transcriptome analysis revealed upregulation of myeloid lineage differentiation-related and type I interferon-related genes. This myeloid-biased differentiation promoted the production and maturation of myeloid cells toward an activated phenotype. Furthermore, depletion of Gr-1+ myeloid cells attenuated the anti-tumor immunity of STING agonist. Our findings reveal the anti-tumor mechanism of systemic administration of STING agonist that involves modulating HSPC differentiation and promoting myeloid cells maturation. Our study may help explain the limited clinical activity of STING agonists administered intratumorally.

Effect of dexamethasone therapy on factors of adhesiveness and coagulation in acute lower limb ischemia

Leukocyte-platelet adhesion during hypoxia, tissue damage, activation of inflammation and coagulation is associated with the expression of ICAM-1 membrane molecules and integrins by blood and tissue cells. At the same time, platelet adhesion receptors determine their adhesion to the endothelium and recruited lymphocytes. The role of platelets in the pathogenesis of ischemic cardiovascular diseases also consists in their ability to modulate both hemostasis and inflammatory reactions, which is accompanied by the secretion of inflammatory mediators and factors that promote the recruitment of leukocytes to tissue damage sites. Purpose of the study: to study the effect of the synthetic glucocorticoid dexamethasone on the expression of adhesion receptors CD18+ and CD54+ on leukocytes, the content of platelets and fibrinogen in the blood of patients with ALLI, the relationship of these indicators with the severity and outcome of the disease.To study the effect of anti-inflammatory therapy, a group of 32 patients treated with dexamethasone was formed; the comparison group was represented by 71 patients with basic therapy, the control group consisted of 15 volunteers. After revascularization, all patients received antiplatelet and anticoagulant therapy. Dexamethasone infusions were carried out in a course of 4 to 6 days after reconstructive surgery. In all patients, the content of C-reactive protein in the blood, the content of platelets and fibrinogen were determined. The number of lymphocytes expressing adhesion molecules ICAM-1 (CD54+) and integrins (CD18+) was counted using the immunocytochemical method. Studies were performed before surgery and on days 1, 3, 7, and 10 after surgery.With exacerbation of ischemia and damage to the endothelium, the accumulation of cytolysis products, the expression of adhesion molecules increases both on endotheliocytes and on inflammatory effector cells – leukocytes and platelets. Adhesion molecules conduct an activation signal inside the cell, which promotes adhesion of leukocytes and platelets to the endothelium, lymphocytic-platelet adhesion, the formation of a parietal thrombus, and possible occlusion of damaged vessels. Increased expression of adhesion molecules is associated with the activation of metabolism, inflammation, coagulation and oxidative stress, stimulates all hematopoietic lineages, including platelets. The level of involvement of cellular reactions in the pathogenesis of the disease affects the effectiveness and duration of treatment, the risk of recurrent thrombosis and death. Anti-inflammatory therapy with dexamethasone contributed to earlier remission, a decrease in the proportion of infectious complications, such as wound suppuration from 10% to 6%, the number of necessary amputations from 32% to 16%, the frequency of deaths from 31% to 6%, and a reduction in hospital stay from 13 days to 10.Inflammation, adhesiveness of effector cells and thrombosis are important factors in the pathogenesis of acute lower limb ischemia. Therapy with dexamethasone helps to reduce the level of systemic inflammatory response, the number of necessary amputations, the number of complications and adverse outcomes in the treatment of ALLI, and reduce the length of stay in the hospital.

A single exercise exertion initiates antioxidant and vascular-protective mechanisms in patients with heart failure

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK (German Centre for Cardiovascular Research). Background Increased systemic inflammation and metabolic dysfunction at rest are observed in heart failure with reduced ejection fraction (HFrEF). Regular (endurance) exercise training can alleviate both. On the other hand, cardiorespiratory exercise testing (CPET) exerts a physical challenge thereby initiating the acute activation of the immune system and several metabolic pathways. Aim To characterize the differences and similarities acute inflammatory and metabolic activation in response to an acute exercise challenge, and their resolution after 2 hours of rest in patients with HFrEF as compared to controls. Methods Participants with HFrEF (n = 16) as well as age and sex matched controls (CON, n = 13) were investigated at baseline (T1), immediately after CPET (T2), and after 2 hours of resting post-CPET (T3). Clinical and physiological parameters, leukocyte profile, plasma cytokines and metabolites were assessed along with inflammatory and metabolic parameters at all three time points. Results and Discussion Cardiovascular risk profile as well as leukocyte, cytokine and metabolic parameters at T1 was similar in CON and HFrEF. Immediately after CPET, lactate, natural killer (NK) and NK-T cell blood counts, among others, were significantly increased in both groups. In HFrEF specifically, platelet aggregates with NK cells, CD8+ cytotoxic T cells and "classical" CD14++CD16-monocytes as well as phosphatidylcholines and triglycerides were increased. After 2h of rest post-CPET, almost all altered parameters returned to baseline in CON. In HFrEF, blood counts and morphological markers of inflammatory effector cell types, including CD8+ T cells and neutrophils remained elevated. Blood levels of inflammatory cytokines were associated to elevated levels of various phosphatidycholines in HFrEF, but not in CON, potentially pointing towards a link to cell death. Blood levels of methionine sulfoxide-to-methionine, declined at T3 versus T1 in both groups, potentially indicating activation of anti-oxidant methionine sulfoxide reductases. In addition, trigonelline, an inhibitor of trimethylamine N-oxide (TMAO) synthesis from choline was elevated by CPET in both groups and this increase correlated inversely with TMAO-to-choline ratio. This might indicate a so far unexplored exercise-induced vascular-protective mechanism by limiting the pro-atherogenic effects of TMAO. Conclusion CPET induced a complex acute immuno-metabolic response, whose restitution to baseline levels differed between HFrEF and healthy controls. Despite longer persistence of pro-inflammatory and metabolic mediators present in the circulation after the end of an acute exercise session, novel anti-oxidant and vascular protective mechanisms of exercise have been identified and appear to be still active in patients with HFrEF.

Коригуючий вплив цитрату германію на репродуктивну функцію самиць зрілих мишей

Fertility decreases with a woman’s age, which is primarily associated with a deterioration in the quality and a decrease in the number of oocytes. Oxidative stress is the most likely factor influencing the decline in oocyte competence. The study of the effect of drugs with antioxidant properties can be a successful strategy for preventive intervention to improve the reproductive potential of women, which is of great medical and social importance. The aim of this work was to evaluate the effect of Ge citrate, obtained by electropulse nanotechnology, on the viability of ovarian granulosa cells, the state of the pro- and antioxidant systems, and the metabolic activity of neutrophils in female old mice. The studies were carried out on mature females of the Albino line (young - at the age of 6-8 weeks, weighing 20-22 g; old - at the age of 8-9 months, weighing 30-34 g). The results showed that in female aged mice, there was a decrease in viability and an increase in necrotic and apoptotic death of ovarian granulosa cells (GC). An increase in the content of the reactive products of 2-thiobarbituric acid in the liver tissue was revealed. With regard to antioxidant protection, a decrease in the level of ceruloplasmin in the blood serum was observed, however, the level of reduced glutathione in the liver homogenate was slightly increased. There was also an increase in the metabolic activity of neutrophils. The use of Ge citrate had a cytoprotective effect on the viability of GC, reducing their necrotic and apoptotic death. In addition, the effect of Ge citrate was accompanied by a significant decrease in lipid peroxidation, regulation of antioxidant protection, and a decrease in the functional activity of inflammatory effector cells, which was confirmed by a decrease in the activation of acid-independent and acid-independent metabolism of neutrophils in the peripheral blood of old mice. In addition, the effect of Ge citrate was accompanied by a significant decrease in lipid peroxidation, the regulation of antioxidant protection, and a decrease in the functional activity of inflammatory effector cells, which was confirmed by a decrease in the activation of oxygen-independent and oxygen-dependent metabolism of peripheral blood neutrophils in old mice. Thus, the results obtained in old female mice showed a positive effect of Ge citrate in preventing the development of oxidative stress, which is considered the main mechanism underlying ovarian aging.

Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses.

Immune aging combines cellular defects in adaptive immunity with the activation of pathways causing a low-inflammatory state. Here we examined the influence of age on the kinetic changes in the epigenomic and transcriptional landscape induced by T cell receptor (TCR) stimulation in naive CD4+ T cells. Despite attenuated TCR signaling in older adults, TCR activation accelerated remodeling of the epigenome and induced transcription factor networks favoring effector cell differentiation. We identified increased phosphorylation of STAT5, at least in part due to aberrant IL-2 receptor and lower HELIOS expression, as upstream regulators. Human HELIOS-deficient, naive CD4+ T cells, when transferred into human-synovium-mouse chimeras, infiltrated tissues more efficiently. Inhibition of IL-2 or STAT5 activity in T cell responses of older adults restored the epigenetic response pattern to the one seen in young adults. In summary, reduced HELIOS expression in non-regulatory naive CD4+ T cells in older adults directs T cell fate decisions toward inflammatory effector cells that infiltrate tissue.

Current knowledge on the early stages of human neutropoiesis.

Polymorphonuclear neutrophils are no longer considered as a homogeneous population of terminally differentiated and short-lived cells that belong to the innate immune system only. In fact, data from the past decades have uncovered that neutrophils exhibit large phenotypic heterogeneity and functional versatility that render them more plastic than previously thought. Hence, their precise role as effector cells in inflammation, in immune response and in other pathophysiological processes, including tumors, needs to be better evaluated. In such a complex scenario, common knowledge of the differentiation of neutrophils in bone marrow refers to lineage precursors, starting from the still poorly defined myeloblasts, and proceeding sequentially to promyelocytes, myelocytes, metamyelocytes, band cells, segmented neutrophils, and mature neutrophils, with each progenitor stage being more mature and better characterized. Thanks to the development and utilization of cutting-edge technologies, novel information about neutrophil precursors at stages earlier than the promyelocytes, hence closer to the hematopoietic stem cells, is emerging. Accordingly, this review discusses the main findings related to the very early precursors of human neutrophils and provides our perspectives on human neutropoiesis.

Protective effect of biogenic selenium nanoparticles against diquat-induced acute toxicity via regulation of gut microbiota and its metabolites.

Selenium nanoparticles (SeNPs) with unique biological properties have been suggested as a safer and more effective platform for delivering of Selenium for biological needs. In this study, we investigated the association between gut microbiota altered by SeNPs supplementation and its metabolites under oxidative stress conditions through 16S rDNA gene sequencing analysis and untargeted metabolomics. The results showed that dietary supplementation with SeNPs attenuated diquat-induced acute toxicity in mice, as demonstrated by lower levels of inflammatory effector cells, and biochemical markers in serum such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH). SeNPs also reversed the perturbed gut microbiota composition induced by diquat, decreased the Firmicutes/Bacteroidetes ratio, and increased the abundance of beneficial bacteria such as Akkermansia, Muribaculaceae, Bacteroides and Parabacteroides. Untargeted fecal metabolomics showed that SeNPs can regulate the production of steroids and steroid derivatives, organonitrogen compounds, pyridines and derivatives and other metabolites. Microbiome-metabolome correlation analysis suggested that Parabacteroides was the key bacteria for the SeNPs intervention, which might upregulate the levels of metabolites such as trimethaphan, emedastine, berberine, desoxycortone, tetrahydrocortisone. This study demonstrated that dietary SeNPs supplementation can extensively modulate the gut microbiota and its metabolism, thereby alleviating diquat-induced acute toxicity.

NK cells are associated with immunometabolic response to a single exercise exertion in heart failure patients

Abstract Background Increased systemic inflammation and metabolic dysfunction are observed in heart failure with reduced ejection fraction (HFrEF). On the other hand, cardiorespiratory exercise testing (CPET) exerts a physical challenge and initiates the activation of the immune system, including acute release of natural killer (NK) cells into the circulation, and several metabolic pathways. Aim To characterize the inflammatory and metabolic alterations of HFrEF patients in response to an acute exercise challenge, and after 2 hours of recovery. Methods Participants with HFrEF (n=16), age and sex matched controls (CON, n=13) were investigated at baseline, immediately after and 2 hours after CPET. Clinical and physiological parameters, leukocyte profile, plasma cytokines and metabolites were assessed along with inflammatory and metabolic parameters at all three time points. NK cell counts and morphological/activation parameters in different contexts were examined. Further, the time-dependent coordination of NK cell numbers post-exercise with tryptophan metabolism and plasma triglycerides were assessed. NK cells were isolated from blood of healthy donors for ex vivo proof-of-principle experiments, including phenotype polarization and NK cell specific tryptophan metabolism. Results Cardiovascular risk profiles as well as leukocyte, cytokine and metabolic parameters at baseline were similar in CON and HFrEF. Immediately after CPET, lactate, and NK T cell blood counts were significantly increased in both groups. In HFrEF but not CON, platelet aggregates with NK cells, CD8+ cytotoxic T cells and “classical” CD14++CD16-monocytes, phosphatidylcholines and triglycerides were increased. After 2h of recovery, almost all altered parameters returned to baseline in CON. In contrast, blood counts and morphological markers of inflammatory effector cell types, including CD8+ T cells and neutrophils remained elevated in HFrEF. NK cells remained elevated after the recovery period and correlated with levels of various triglyceride species in the HFrEF patients. Tryptophan levels in plasma were reduced by acute exercise and the kynurenine to tryptophan ratio was increased and correlated with increase in NK and NK-T cell counts, as well as IL-12 plasma levels. Treatment with IL-12 led to increased synthesis of kynurenine from tryptophan, expression of indoleamine 2,3-dioxygenase and abundance of regulatory CD56bri NK cell phenotypes ex vivo. Secretome of untreated NK cells impaired cellular respiration, increased glycolysis/oxidation ratio in skeletal muscle cells, and increased the release of triglycerides from hepatocarcinoma cells. Conclusion CPET induced a complex acute immunometabolic response, whose restitution to baseline levels differed between HFrEF and healthy controls. Exercise-induced changes in NK cell metabolism and phenotype shift might modulate cellular respiration in myocytes and release of triglycerides by hepatocytes in HFrEF and in CON. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK (German Centre for Cardiovascular Research)

Role of macrophages in prevention and control of diseases and their upregulation through cowpathy

Mammalian macrophages are present from mid gestation onwards, helping to maintain physiologic homeostasis. During embryonic development in the mouse, macrophages emerge from yolk sac and foetal liver progenitors and survive as diverse, self-renewing tissue-resident populations in many organs. After birth, bone marrow-derived blood monocytes are recruited to replenish tissue resident populations and to meet additional demands during inflammation, infection, and metabolic changes. Signals that generate and maintain inflammation, as well as signals that shut down the process, are normally controlled carefully in the inflammatory process. Inflammation goes uncontrolled when the two signals are out of sync, causing cellular and tissue damage. Macrophages are a key component of the mononuclear phagocyte system, which includes blood monocytes and tissue macrophages. Monocytes travel from the bloodstream into various organs and convert into macrophages. Antigen presentation, phagocytosis, and immunomodulation through the production of different cytokines and growth factors are three key functions of macrophages in inflammation. Macrophages are critical in the onset, maintenance, and resolution of inflammation. During the inflammatory process, they are activated and deactivated. Cytokines (interferon, granulocyte-monocyte colony stimulating factor, and tumour necrosis factor), bacterial lipopolysaccharide, extracellular matrix proteins, and other chemical mediators are all examples of activation signals. The elimination or deactivation of mediators and inflammatory effector cells inhibits inflammation, allowing the host to heal damaged tissues. Anti-inflammatory cytokines (interleukin 10 and transforming growth factor ß) and cytokine antagonists, which are primarily generated by macrophages, deactivate active macrophages. Macrophages are involved in the inflammatory process' autoregulatory loop. We outline macrophage activities in inflammation and healing in response to

OX40 Expression in Eosinophils Aggravates OVA-Induced Eosinophilic Gastroenteritis.

Background & AimsEosinophils are the main inflammatory effector cells that damage gastrointestinal tissue in eosinophilic gastrointestinal diseases (EGIDs). Activation of the OX40 pathway aggravates allergic diseases, such as asthma, but it is not clear whether OX40 is expressed in eosinophils to regulate inflammation in EGIDs. In this study, we assessed the expression and effect of OX40 on eosinophils in WT and Ox40-/- eosinophilic gastroenteritis (EGE) mice.MethodsEosinophil infiltration, ovalbumin (OVA)-specific Ig production, OX40 expression and inflammatory factor levels in the intestine and bone marrow (BM) were investigated to evaluate inflammation.ResultsWe confirmed that OVA-challenged mice produced high levels of Ox40, Mbp, Ccl11, Il5, Il4, Il13, and Il6 mRNA and a low level of Ifng mRNA in the intestine. Increased eosinophils were observed in intestinal and lymph tissues, accompanied by significantly upregulated OX40 and Type 2 cytokine production in eosinophils of EGE mice. Ox40 deficiency ameliorated OVA-induced inflammation, eosinophil infiltration, and cytokine production in the intestine. Consistently, Ox40-/ - eosinophils exhibited decreased proliferation and proinflammatory function. The stimulation of the agonistic anti-OX40 antibody, OX86, promoted the effect of OX40 on eosinophils. The present study also showed that Ox40 deficiency dampened the Traf2/6-related NF-κB signaling pathway in eosinophils.ConclusionsOX40 may play a critical role in the progress of OVA-induced EGE by promoting the maturation and function of eosinophils via the Traf2/6-related NF-κB signaling pathway.

Angiogenesis, Lymphangiogenesis, and Inflammation in Chronic Obstructive Pulmonary Disease (COPD): Few Certainties and Many Outstanding Questions.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation, predominantly affecting the lung parenchyma and peripheral airways, that results in progressive and irreversible airflow obstruction. COPD development is promoted by persistent pulmonary inflammation in response to several stimuli (e.g., cigarette smoke, bacterial and viral infections, air pollution, etc.). Angiogenesis, the formation of new blood vessels, and lymphangiogenesis, the formation of new lymphatic vessels, are features of airway inflammation in COPD. There is compelling evidence that effector cells of inflammation (lung-resident macrophages and mast cells and infiltrating neutrophils, eosinophils, basophils, lymphocytes, etc.) are major sources of a vast array of angiogenic (e.g., vascular endothelial growth factor-A (VEGF-A), angiopoietins) and/or lymphangiogenic factors (VEGF-C, -D). Further, structural cells, including bronchial and alveolar epithelial cells, endothelial cells, fibroblasts/myofibroblasts, and airway smooth muscle cells, can contribute to inflammation and angiogenesis in COPD. Although there is evidence that alterations of angiogenesis and, to a lesser extent, lymphangiogenesis, are associated with COPD, there are still many unanswered questions.

Cell surface–tethered IL-12 repolarizes the tumor immune microenvironment to enhance the efficacy of adoptive T cell therapy

Immune-activating cytokines such as interleukin-12 (IL-12) hold strong potential for cancer immunotherapy but have been limited by high systemic toxicities. We describe here an approach to safely harness cytokine biology for adoptive cell therapy through uniform and dose-controlled tethering onto the surface of the adoptively transferred cells. Tumor-specific T cells tethered with IL-12 showed superior antitumor efficacy across multiple cell therapy models compared to conventional systemic IL-12 coadministration. Mechanistically, the IL-12–tethered T cells supported a strong safety profile by driving interferon-γ production and adoptively transferred T cell activity preferentially in the tumor. Immune profiling revealed that the tethered IL-12 reshaped the suppressive tumor immune microenvironment, including triggering a pronounced repolarization of monocytic myeloid-derived suppressor cells into activated, inflammatory effector cells that further supported antitumor activity. This tethering approach thus holds strong promise for harnessing and directing potent immunomodulatory cytokines for cell therapies while limiting systemic toxicities.

Imidazopyrazines as New Anti‐inflammatory Agents: Discovery and Biological Activity Research in vitro and in vivo

AbstractA series of imidazopyrazine derivatives were synthesized, and evaluated for their anti‐inflammatory activity in vitro and in vivo using RAW264.7 cells model and Zebrafish Traumatic Infection Inflammation model. The results in vitro showed that the compounds had significant inhibitory effect on inflammatory factor interleukin 6 (IL6), and N‐ (3 ‐( 4‐ ((1,1‐dioxidothiomorpholino) methyl)phenyl) imidazo [1,5‐a] pyrazin‐6‐yl) cyclopropanecarboxamide A1 the best activity, which was significantly different from that of the lipopolysaccharide (LPS) control group (P<0.03). The experiment of anti‐inflammatory activity in vivo indicated that compound A1 showed obvious aggregation inhibitory activity on inflammatory effector cells which was significantly different from that in the tail‐cutting control group (P<0.03). When the concentration of the compound was 160 μg/mL, the inhibitory activity of compound A1 was better than that of dexamethasone positive control group (P<0.05). This study could supply some anti‐inflammatory leading structure and possible mechanism for studying and developing new anti‐inflammatory agents.

The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients.

Background: Severe coronavirus disease 2019 (COVID-19) causes a strong inflammatory response. To obtain an overview of inflammatory mediators and effector cells, we studied 25 intensive-care-unit patients during the timeframe after off-label chloroquine treatment and before an introduction of immunomodulatory drugs. Material and methods: Blood samples were weekly examined with flow cytometry (FCM) for surface and intracytoplasmic markers, cytokine assays were analyzed for circulating interleukins (ILs), and blood smears were evaluated for morphological changes. Samples from healthy volunteers were used for comparison. Organ function data and 30-day mortality were obtained from medical records. Results: Compared to that of the healthy control group, the expression levels of leukocyte surface markers, i.e., the cluster of differentiation (CD) markers CD2, CD4, CD8, CD158d, CD25, CD127, and CD19, were lower (p < 0.001), while those of leukocytes expressing CD33 were increased (p < 0.05). An aberrant expression of CD158d on granulocytes was found on parts of the granulocyte population. The expression levels of intracellular tumor necrosis factor alpha (TNFα) and IL-1 receptor type 2 in leukocytes were higher (p < 0.001) as well as plasma levels of TNFα, IL-2, IL-6, IL-8, IL-10 (p < 0.001), interferon gamma (IFNγ) (p < 0.01), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.05). The expression levels of CD33+ leukocytes and circulating IL-6 were higher (p < 0.05) among patients with arterial oxygen partial pressure-to-fractional inspired oxygen (PaO2/FiO2) ratios below 13.3 kPa compared to in the remaining patients. The expression levels of TNFα, IL-2, IL-4, IL-6, IL-8, and IL-10 were higher in patients treated with continuous renal replacement therapy (CRRT) (p < 0.05), and the levels of the maximum plasma creatinine and TNFα Spearman’s rank-order correlation coefficient (rho = 0.51, p < 0.05) and IL-8 (rho = 0.44, p < 0.05) correlated. Blood smears revealed neutrophil dysplasia with pseudo-Pelger forms being most common. Conclusion: These findings suggest that patients with severe COVID-19, in addition to augmented ILs, lymphopenia, and increased granulocytes, also had effects on the bone marrow.

Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.

Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. Here, we demonstrated that circulating CD4+ T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127- killer cell lectin-like receptor G1+ . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4+ T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.